Canonical versus non-canonical transsynaptic signaling of neuroligin 3 tunes development of sociality in mice

• DOI: 10.1038/s41467-021-22059-6
• Publication Date: 2021-03-23T11:04:44Z
• Authors: Tomoyuki Yoshida; Atsushi Yamagata; Ayako Imai; Juhyon Kim; Hironori Izumi; Shogo Nakashima; Tomoko Shiroshima; Asami Maeda; Shiho Iwasawa-Oka...; Kenji Azechi; Fumina Osaka; Takashi Saitoh; Katsumi Maenaka; Takashi Shimada; Yuko Fukata; Masaki Fukata; Jumpei Matsumoto; Hisao Nishijo; Keizo Takao; Shinji Tanaka; Shigeo Okabe; Katsuhiko Tabuchi; Takeshi Uemura; Masayoshi Mishina; Hisashi Mori; Shuya Fukai
• Keywords: Neuroligin; Non canonical

Abstract Neuroligin 3 (NLGN3) and neurexins (NRXNs) constitute a canonical transsynaptic cell-adhesion pair, which has been implicated in autism. In autism spectrum disorder (ASD) development of sociality can be impaired. However, the molecular mechanism underlying NLGN3-mediated social is unclear. Here, we identify non-canonical interactions between NLGN3 protein tyrosine phosphatase δ (PTPδ) splice variants, competing with NRXN binding. NLGN3-PTPδ complex structure revealed splicing-dependent interaction mode competition PTPδ NRXNs. Mice carrying mutation that selectively impairs NLGN3-NRXN show increased sociability, whereas mice where impaired exhibit behavior enhanced motor learning, imbalance excitatory/inhibitory synaptic expressions, as reported Nlgn3 R451C model. At neuronal level, autism-related causes selective impairment pathway. Our findings suggest pathways compete regulate sociality.